CN112279841A - Antiviral andrographolide derivative and preparation method thereof - Google Patents
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- ethyl acetate
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- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical class C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 title claims abstract description 42
- 230000000840 anti-viral effect Effects 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title abstract description 9
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims abstract description 26
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
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- 102000053602 DNA Human genes 0.000 description 2
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
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- 229920002477 rna polymer Polymers 0.000 description 2
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- 238000005303 weighing Methods 0.000 description 2
- 229940126673 western medicines Drugs 0.000 description 2
- YTHKMAIVPFVDNU-GPTWTFMPSA-N 4-[[(1r,2r,4ar,5r,8as)-2-(3-carboxypropanoyloxy)-1,4a-dimethyl-6-methylidene-5-[(e)-2-(5-oxo-2h-furan-4-yl)ethenyl]-3,4,5,7,8,8a-hexahydro-2h-naphthalen-1-yl]methoxy]-4-oxobutanoic acid Chemical compound C(/[C@@H]1C(=C)CC[C@H]2[C@@]1(C)CC[C@H]([C@]2(COC(=O)CCC(O)=O)C)OC(=O)CCC(O)=O)=C\C1=CCOC1=O YTHKMAIVPFVDNU-GPTWTFMPSA-N 0.000 description 1
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- 241001465754 Metazoa Species 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
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- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229960001280 amantadine hydrochloride Drugs 0.000 description 1
- WOLHOYHSEKDWQH-UHFFFAOYSA-N amantadine hydrochloride Chemical compound [Cl-].C1C(C2)CC3CC2CC1([NH3+])C3 WOLHOYHSEKDWQH-UHFFFAOYSA-N 0.000 description 1
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- BITYAPCSNKJESK-UHFFFAOYSA-N potassiosodium Chemical compound [Na].[K] BITYAPCSNKJESK-UHFFFAOYSA-N 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Virology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
The invention discloses an antiviral andrographolide derivative and a preparation method thereof, wherein the preparation method comprises the following steps: andrographolide and N, N' -carbonyldiimidazole are added into an organic solvent, a novel andrographolide derivative is obtained through a one-step method, and because imidazole groups are easily dissolved in water, the solubility of the obtained compound is remarkably improved, so that the bioavailability of the compound is improved; the pathological experiment shows that the andrographolide derivative can obviously reduce the pneumonia of a virus mouse, and the treatment effect is equivalent to that of ribavirin, even better than the anti-pneumonia virus activity of monomer substances of andrographolide and N, N' -carbonyldiimidazole; the preparation method provided by the invention is simple, the raw materials are easy to obtain, the yield is high, the operation condition is mild, the andrographolide derivative can be conveniently prepared, and the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of chemical drug synthesis, and relates to an antiviral andrographolide derivative and a preparation method thereof.
Background
The virus, the smallest of the pathogenic microorganisms, is propagated inside the cell, and has a core of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA), and a shell of protein, which has no cellular structure. Currently, the main clinical treatments for viral infections are the use of broad-spectrum antiviral drugs and immunomodulators, such as acyclovir, ribavirin, polyinosinic acid, amantadine hydrochloride, and the like. Most antiviral drugs are viral polymerase inhibitors, which are mainly used to fight against or destroy viral infections, such as directly inhibiting or killing viruses, interfering with viral adsorption, enhancing host antiviral ability, etc. Although the western medicines are safe from the current clinically used or to be applied antiviral medicines, the antiviral medicines have simple virus structures and low protein content, so that the antiviral medicines form stronger drug resistance after long-term use, and the treatment effect of the clinically common antiviral medicines is limited.
Recent researches have shown that some natural product extracts and derivatives thereof have antiviral effects, and the extracts not only have the antiviral effect of western medicines, but also can reduce the side effects in the using process.
Andrographolide is an effective component of natural plant andrographis paniculata, has the effects of clearing away heat and toxic materials, diminishing inflammation and relieving pain, has special curative effect on bacterial and viral upper respiratory tract infection, and is known as a natural antibiotic medicine. The antiviral properties of andrographolide and its derivatives have been studied and studied. For example, "potassium sodium andrographolide disuccinate" as an active ingredient and "potassium dehydroandrographolide succinate" as an active ingredient. Because the biological agents are potassium salts, the long-term administration of the medicine can cause the serum potassium to be overhigh, has the inhibition effect on cardiac muscle, and simultaneously can excite the cardiac muscle to stop the heartbeat in the contraction period. Therefore, there is a need to find a drug with better antiviral effect and less side effects.
Disclosure of Invention
In view of the above problems, the present invention provides an antiviral andrographolide derivative, which has a molecular structure of formula (I):
another objective of the present invention is to provide a method for preparing an antiviral andrographolide derivative, comprising the following steps:
dissolving andrographolide in an organic solvent, reacting at 5-10 ℃ for 4-6 hours, adding N, N' -carbonyldiimidazole, detecting the completion of the reaction by TLC, recovering the solvent under reduced pressure, adding absolute ethyl alcohol, stirring, filtering, purifying filtrate by silica gel column chromatography, collecting eluent, concentrating, extracting concentrated solution with ethyl acetate, crystallizing, filtering, drying in vacuum and obtaining a target product;
the organic solvent is tetrahydrofuran, methanol, diethyl ether or carbon tetrachloride;
the dosage of the N, N' -carbonyl diimidazole is 30 percent of that of the andrographolide;
the eluent is a mixed solution of petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is 2: 1.
According to a preferred embodiment of the above preparation method, the method comprises the following steps:
dissolving andrographolide in tetrahydrofuran, reacting at 5-10 ℃ for 4-6 hours, adding N, N' -carbonyldiimidazole, detecting reaction completion by TLC, recovering solvent under reduced pressure, adding absolute ethyl alcohol, stirring, filtering, performing silica gel column chromatography on filtrate under the condition of an eluent ratio of petroleum ether to ethyl acetate of 2:1, collecting eluent, concentrating, extracting concentrated solution with ethyl acetate, crystallizing, filtering, and drying in vacuum to obtain a target product.
Compared with the prior art, the invention has the beneficial effects that:
(1) according to the invention, andrographolide and N, N' -carbonyldiimidazole are reacted to obtain a novel antiviral andrographolide derivative, and because imidazole groups are easily dissolved in water, the water solubility of the obtained compound can be obviously improved, so that the bioavailability of the compound is improved; the pathological experiment shows that the andrographolide derivative can obviously reduce pneumonia of virus mice, has the same treatment effect as ribavirin, and has better anti-pneumonia virus activity than andrographolide.
(2) The andrographolide derivative provided by the invention has the advantages of simple preparation method, easily obtained raw materials, high yield and mild operation conditions, can be conveniently prepared, and is suitable for industrial production.
Drawings
FIG. 1: example 4 nuclear magnetic resonance hydrogen spectra of antiviral andrographolide derivatives and methods of preparation thereof.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments for the purpose of making the objects, technical solutions and advantages of the present invention more apparent, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples.
Example 1
Adding 20g of andrographolide into a 100mL single-neck bottle, adding 40mL of tetrahydrofuran under the protection of nitrogen, stirring for dissolving, adjusting the temperature to 5 ℃, adding 6g N, N' -carbonyldiimidazole in batches, carrying out reflux reaction for 4-6 h, detecting by TLC to finish the reaction, stopping the reaction, concentrating and recovering the solvent at 60 ℃ under reduced pressure, adding absolute ethyl alcohol, stirring for dissolving and filtering, carrying out silica gel column chromatography on the filtrate at the volume ratio of petroleum ether to ethyl acetate of 2:1, concentrating the obtained chromatographic solution, extracting with ethyl acetate, concentrating the ethyl acetate extract, crystallizing, filtering, and drying in vacuum to obtain the target product, wherein the yield is 79.34%.
Example 2
Adding 20g of andrographolide into a 100mL single-neck bottle, adding 40mL of tetrahydrofuran under the protection of nitrogen, stirring for dissolving, adjusting the temperature to 7 ℃, adding 6g N, N' -carbonyldiimidazole in batches, carrying out reflux reaction for 4-6 h, detecting by TLC to finish the reaction, stopping the reaction, concentrating and recovering the solvent at 60 ℃ under reduced pressure, adding absolute ethyl alcohol, stirring for dissolving and filtering, carrying out silica gel column chromatography on the filtrate at the volume ratio of petroleum ether to ethyl acetate of 2:1, concentrating the obtained chromatographic solution, extracting with ethyl acetate, concentrating the ethyl acetate extract, crystallizing, filtering, and drying in vacuum to obtain the target product, wherein the yield is 80.56%.
Example 3
Adding 20g of andrographolide into a 100mL single-neck bottle, adding 40mL of tetrahydrofuran under the protection of nitrogen, stirring for dissolving, adjusting the temperature to 9 ℃, adding 6g N, N' -carbonyldiimidazole in batches, carrying out reflux reaction for 4-6 h, detecting by TLC to finish the reaction, stopping the reaction, concentrating and recovering the solvent at 60 ℃ under reduced pressure, adding absolute ethyl alcohol, stirring for dissolving and filtering, carrying out silica gel column chromatography on the filtrate at the volume ratio of petroleum ether to ethyl acetate of 2:1, concentrating the obtained chromatographic solution, extracting with ethyl acetate, concentrating the ethyl acetate extract, crystallizing, filtering, and drying in vacuum to obtain the target product, wherein the yield is 80.77%.
Example 4
Adding 20g of andrographolide into a 100mL single-neck bottle, adding 40mL of tetrahydrofuran under the protection of nitrogen, stirring for dissolving, adjusting the temperature to 10 ℃, adding 6g N, N' -carbonyldiimidazole in batches, carrying out reflux reaction for 4-6 h, detecting by TLC to finish the reaction, stopping the reaction, concentrating and recovering the solvent at 60 ℃ under reduced pressure, adding absolute ethyl alcohol, stirring for dissolving and filtering, carrying out silica gel column chromatography on the filtrate at the volume ratio of petroleum ether to ethyl acetate of 2:1, concentrating the obtained chromatographic solution, extracting with ethyl acetate, concentrating the ethyl acetate extract, crystallizing, filtering, and drying in vacuum to obtain the target product, wherein the yield is 81.04%.
Example 5 Water solubility testing of Compounds of the invention
0.1g of the compound of example 1 to 4 was weighed into a test tube, 10.0mL of purified water was added, the test tube was shaken every 5min at room temperature for 30 seconds, the dissolution was observed after 30min, the amount of the solvent was recorded, the test results were converted to standard solubility (25 ℃), and the test results are shown in Table 1.
TABLE 1 solubility and yield of the compounds of examples 1-4
The result shows that compared with andrographolide, the water solubility of the andrographolide derivative is obviously improved; as can be seen from comparative examples 1 to 4, the solubility thereof was higher as the reaction temperature condition was increased; when the reaction temperature was controlled at 10 ℃, the solubility reached 0.40mg/mL, which was the highest solubility in the above 4 groups of examples.
And (3) nuclear magnetic resonance hydrogen spectrum detection:
in the above-mentioned examples 1 to 4, samples of different groups were sequentially placed in sample tubes, and 0.5ml of DCL3 (deuterated chloroform) was injected into the sample tubes by using a syringe to dissolve the samples sufficiently. Each group of samples is required to be fully mixed with the reagent, the solution is clear and transparent, and has no suspended matters or other impurities, and a nuclear magnetic resonance hydrogen spectrogram is respectively obtained through nuclear magnetic resonance identification; among them, the most representative results of the hydrogen nuclear magnetic resonance spectroscopy of example 4 are shown in FIG. 1.
Experimental example 6 antiviral action of the derivative of the present invention
The test animals were: mouse, Kunming, SPF grade, male and female, body weight 14+1 g.
Experimental groups: the drug adopted in the in vivo test of the mice is the andrographolide derivative in example 1-4, and each feeding is administered with 0.5mL once a day.
Positive control group: ribavirin, administered as a 0.88g/kg gavage, 0.5mL each, once a day.
Virus: storing influenza virus A FM1 at-70 deg.C.
The method comprises the following steps: mice were randomly divided into 7 groups by body weight, which were a normal control group (control group 1), a virus control group (control group 2), a ribavirin control group (control group 3), an andrographolide group (control group 4), and an experimental group, respectively. Except for the normal control group, mice were lightly anesthetized with ether and 15 LDs were administered50Influenza virus liquid is dripped into the nose to infect, 0.5mL each. Feeding once a day before infection, 0.5 mL/mouse every time for 5 consecutive days, feeding a control group with distilled water under the same condition, weighing the weight of the mouse on the 6 th day, dissecting, picking the whole lung, weighing, calculating the lung index value, and calculating the lung index inhibition rate according to the following formula:
the lung index inhibition rate is (mean value of lung index of virus control group-mean value of lung index of experiment group)/mean value of lung index of virus control group x 100%. Results are shown in table 2, data were statistically processed using the inter-group t-test.
TABLE 2 inhibitory Effect of the derivatives of the present invention on influenza viral pneumonia in influenza mice
Table 2 the results show that: the andrographolide derivative can obviously reduce pneumonia of virus mice, has a treatment effect equivalent to that of ribavirin, and has better anti-pneumonia virus activity than andrographolide; it can be seen from comparative examples 1 to 4 that the andrographolide derivative of example 4 showed relatively best antiviral activity with the increase of the reaction temperature, which indicates that the structure of the prepared andrographolide derivative is relatively stable and the prepared andrographolide derivative exerts relatively best biological activity when the reaction temperature is controlled at 10 ℃. In conclusion, the compound has great prospect for preparing novel antiviral drugs.
Claims (3)
1. An antiviral andrographolide derivative, wherein the antiviral andrographolide derivative has a molecular structure of formula (I):
2. the method for preparing anti-viral andrographolide derivatives according to claim 1, comprising the steps of:
dissolving andrographolide in an organic solvent, reacting at 5-10 ℃ for 4-6 hours, adding N, N' -carbonyldiimidazole, detecting the completion of the reaction by TLC, recovering the solvent under reduced pressure, adding absolute ethyl alcohol, stirring, filtering, purifying filtrate by silica gel column chromatography, collecting eluent, concentrating, extracting concentrated solution with ethyl acetate, crystallizing, filtering, drying in vacuum and obtaining a target product;
the organic solvent is tetrahydrofuran, methanol, diethyl ether or carbon tetrachloride;
the dosage of the N, N' -carbonyl diimidazole is 30 percent of that of the andrographolide;
the eluent is a mixed solution of petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is 2: 1.
3. The method of claim 2, comprising the steps of:
dissolving andrographolide in tetrahydrofuran, reacting at 5-10 ℃ for 4-6 hours, adding N, N' -carbonyldiimidazole, detecting reaction completion by TLC, recovering solvent under reduced pressure, adding absolute ethyl alcohol, stirring, filtering, performing silica gel column chromatography on filtrate under the condition of an eluent ratio of petroleum ether to ethyl acetate of 2:1, collecting eluent, concentrating, extracting concentrated solution with ethyl acetate, crystallizing, filtering, and drying in vacuum to obtain a target product.
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| CN202011173744.5A Pending CN112279841A (en) | 2020-10-28 | 2020-10-28 | Antiviral andrographolide derivative and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113173895A (en) * | 2021-05-12 | 2021-07-27 | 籍建亚 | Andrographolide derivative for resisting influenza virus infection and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101628903A (en) * | 2008-07-15 | 2010-01-20 | 刘力 | Defervescence anti-inflammatory and anti-infection medicine with immunization function, preparation and application thereof |
| CN103739576A (en) * | 2014-01-24 | 2014-04-23 | 北京普瑞博思投资有限公司 | Novel antiviral andrographolide derivative and preparation method and application thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101628903A (en) * | 2008-07-15 | 2010-01-20 | 刘力 | Defervescence anti-inflammatory and anti-infection medicine with immunization function, preparation and application thereof |
| CN103739576A (en) * | 2014-01-24 | 2014-04-23 | 北京普瑞博思投资有限公司 | Novel antiviral andrographolide derivative and preparation method and application thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113173895A (en) * | 2021-05-12 | 2021-07-27 | 籍建亚 | Andrographolide derivative for resisting influenza virus infection and preparation method thereof |
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Application publication date: 20210129 |